Cisplatin is a widely used chemotherapeutic agent, but which produces dose-limiting side effects, such as nephrotoxicity and ototoxicity. Recent data from our laboratory indicate that the transplatin, an inactive isomer of cisplatin, reduces cisplatin induced death of cochlear hair cell in culture. This effect is presumably mediated by inhibition of cisplatin-dependent generation of reactive oxygen species (ROS) through the unique cochlear NADPH oxidase isoform, N0X3, the major source of ROS generation in the cochlea. Transplatin also decreased cisplatin-induced intracellular Ca2+ release, induction of stress proteins such as transient receptor potential vanilloid receptor 1 (TRPV1) and kidney injury molecule 1 (KIM-1). Importantly, transplatin did not inhibit the killing of prostate cancer cells by cisplatin. These findings suggest that transplatin could be useful a useful drug to limit cisplatin ototoxicity. We would test the overall hypothesis that transplatin is effective against cisplatin ototoxicity in rats. These studies will include three specific aims.
Specific Aim 1 will determine the effectiveness of transplatin against cisplatin-induced hearing loss, using either systemic administration or by direct round window application of transplatin. Otoprotection will be assessed by auditory brain stem responses (ABRs) and by assessing the morphology of cochlear inner and outer hair cells, using scanning electron microscopy (SEM). In addition expression of NADPH oxidase subunlts (such as N0X3, Rac1, p22phox and p67phox), stress proteins (such as TRPV1, KIM-1, heat shock proteins and heat shock factor) and apoptotic proteins will also be assessed.
Specific Aim 2 will determine the optimal dose and time of transplatin administration linked to optimal ototprotection and to determine whether transplatin is effective following cisplatin administration.
Specific Aim 3 will determine whether transplatin interferes with the growth inhibitory action of cisplatin against breast and prostate cancer tumors in severe combined immunodeficient (SCID) mice. These studies will provide significant data and form the basis of the clinical application of transplatin as a novel therapy for drug-induced ototoxicity. The relatively low toxicity of transplatin could hasten the timeline from bench to bedside use of this drug in cancer patients.
Cisplatin-related hearing loss is a major problem among cancer patients treated with this drug, particularly in children. If we are able to find a novel method to prevent the hearing loss without compromising the effectiveness of the chemotherapy, it would be a major breakthrough. Such a treatment could improve the quality of life of cancer patients who would otherwise face many years of poor communication because of hearing loss caused by cisplatin treatment.
